Sellars is best known as a critic of foundationalistepistemology, but his philosophical oeuvre is more generally directed toward the ultimate goal of reconciling intuitive ways of describing the world (both those of common sense and traditional philosophy) with a thoroughly naturalist, scientific account of reality. He is widely regarded both for great sophistication of argument and for his assimilation of many and diverse subjects in pursuit of a synoptic vision. He was perhaps the first philosopher to combine effectively elements of American Pragmatism with elements of British and American analytic philosophy and Austrian and German logical positivism. He worked on a broad range of topics in both philosophy and its history. Sellars's writings reputedly make for hard reading, perhaps because of his insistence on writing for the ages. He deemed the history of philosophy to be the lingua franca of philosophy; hence his writings engaged not only with the philosophy of his time, but also with that of the entire past.

Robert Brandom named Sellars and Willard van Orman Quine as the two most profound and important philosophers of their generation. Sellars' goal of a synoptic philosophy that unites the everyday and scientific views of reality is the foundation and archetype of what is sometimes called the "Pittsburgh School", whose members include Brandom, John McDowell, and John Haugeland. Other philosophers strongly influenced by Sellars span the full spectrum of contemporary English-speaking philosophy, from neopragmatism (Richard Rorty) to eliminative materialism (Paul Churchland) to rationalism (Laurence BonJour). Sellars' philosophical heirs also include Hector-Neri Castaneda, Bruce Aune, Jay Rosenberg, Johanna Seibt, Andrew Chrucky, Jeffrey Sicha, Pedro Amaral, Thomas Vinci, Willem de Vries, and Timm Triplett.

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Sellars' most famous work is the lengthy and difficult paper, Empiricism and the Philosophy of Mind, a sustained discussion of what he called "The Myth of the Given," which consists of the claim, central to both phenomenology and sense-data theories of knowledge, that we can know things about our perceptual experiences independently of and in some important sense prior to the conceptual apparatus which we use to perceive objects. Sellars targets several theories at once, especially C.I. Lewis' Kantian pragmatism and Rudolf Carnap's positivism. Sellars then goes on to construct "The Myth of Jones," a philosophical parable to explain how thoughts, intelligent action, and even subjective inner experience can be attributed to people within a strict behaviorist worldview. Sellars calls his fictional tribe "Ryleans," named after Gilbert Ryle, whose The Concept of Mind he specifically wanted to address. Sellars' idea of "myth," heavily influenced by Ernst Cassirer, is by no means a necessarily negative one; a myth is something that can be useful or otherwise, rather than true or false. One of Sellars' most central goals, which his later work described as Kantian, was reconciling the conceptual behavior of the "space of reasons" with the concept of a subjective sense experience. Some think this approach blurs the received empirical distinction between knower and known, subject and object, as well as entailing "linguistic idealism."

In his Philosophy and the Scientific Image of Man, Sellars distinguishes between the "manifest image" and the "scientific image" of the world. The manifest image describes the way the world stands according to the language we ordinarily use in interacting with it (which includes, for example, intentions, thoughts, and appearances). The scientific image describes the world in terms of the theoretical physical sciences, including notions such as causality and theories about particles and forces. While the two images sometimes complement one another (e.g., the manifest image includes practical or moral claims, whereas the scientific image does not), they sometimes conflict, as when physics tells us that apparently solid objects are mostly made of empty space. Sellars attempts to outline a synoptic vision, wherein the scientific image takes ultimate precedence in cases of irreconciliable conflict, at least with respect to empirical descriptions and explanations.

Sellars coined certain now-common idioms in philosophy, such as the "space of reasons". This idiom refers to two things. It:

Describes the conceptual and behavioral web of language that humans use to get intelligently around their world,

Denotes the fact that talk of reasons, justification, and intention is not the same as, and cannot necessarily be mapped onto, talk of causes and effects in the sense that physical science speaks of them.

(2) corresponds in part to the Sellarsian distinction between the manifest image and the scientific image.